Hypertension is one of the most common cardiovascular diseases. Typically, a person is diagnosed with hypertension when his/her blood pressure is in a range of 140/90 mmHg. Recently, the incidence of lifestyle-related diseases such as hypertension has rapidly increased. As hypertension may result in the occurrence of acute heart diseases or myocardial infarction, there is a continued need for development of a more effective antihypertensive agent.
According to various clinical trials of antihypertensive agents, it was found that lowering of blood pressure of hypertensive patients leads to a decrease in mortality and morbidity of heart diseases or myocardial infarction (Collins R, Peto R, MacMahon S, Hebert P, Fiebach N H, Eberlein K A, Godwin J, Qizilbash N, Taylor J O, Hennekens C H, Lancet 1990, 335(8693):827-38). Although a variety of drugs have been used and administered for the purpose of treating such a clinical condition, suitable control of blood pressure is not always successful (Waeber B, Brunner H R, Am. J. Hypertens 1997. 10(7 Pt 2):131S-137S).
Among various applicable administration modes of antihypertensive drugs, a combination preparation or combination therapy of drugs is one method for achieving desired therapeutic results. On the other hand, arbitrary selection of various classes of antihypertensive agents for application of drugs to combination therapy prescription does not always provide help to achieve a desired blood pressure level in a hypertensive mammal including a human (MacGregor G A, Markandu N D, Banks R A, Bayliss J. Roulston J E, Jones J C, Br Med J (Clin Res Ed), 284 (6317): 693-6).
To this end, there is an obvious need for further development of therapeutic methods, combination preparations and pharmaceutical compositions against hypertension.
Fimasartan, which is chemically defined as 2-n-butyl-5-dimethylaminothiocarbonyl-methyl-6-methyl-3-[[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]pyrimidin-4(3H)-one and has the following structural formula:
is an antihypertensive agent of the angiotensin II receptor blocker (ARB) class and has currently been approved as a pharmaceutical product under brand name of KANARB®.
According to the randomized double-blind clinical testing conducted for the comparison of antihypertensive effects in patients with mild to moderate essential hypertension, at a dose of 60 mg to 120 mg of drugs between Fimasartan potassium and Losartan which is a representative compound of the ARB class, it was demonstrated that antihypertensive effects in terms of changes in diastolic blood pressure (DBP) in the sitting position at Week 12 of drug administration were respectively −11.26±7.53 mmHg for the Fimasartan-treated group and −8.56±7.72 mmHg for the Losartan-treated group, relative to a baseline, thus showing that antihypertensive effects after 12- or 24-week administration were higher in Fimasartan than Losartan (A Randomized, Double-blind, Losartan-controlled, Parallel Group Comparison Dose Titration Clinical Study to Evaluate the Antihypertensive Efficacy and Safety of Fimasartan (BR-A-657.K) 60 mg˜120 mg in Patients with Mild to Moderate Essential Hypertension (Phase III)).
Amlodipine is a calcium channel blocker (CCB), and blocks an inflow of calcium ions to cell membranes of cardiac and peripheral vascular smooth muscles and therefore directly relaxes vascular smooth muscles to exhibit antihypertensive effects. Although the action mechanism by which Amlodipine mitigates angina pectoris has not been fully understood, it was found that the following two action mechanisms function to relieve ischemic symptoms.
First, Amlodipine dilates peripheral arteries to decrease the total peripheral resistance (after-load), thus leading to decreased cardiac work, and stabilizes a heart rate to decrease cardiac energy consumption and oxygen demand.
Second, it is believed that Amlodipine dilates main coronary arteries and other coronary arterioles of ischemic lesions and normal regions. Such vasodilation plays a role to increase delivery of oxygen to myocardial ischemic lesions of patients with coronary artery convulsion.
Although active research for the treatment of hypertension has recently been focused on a combination preparation of Amlodipine, which is a calcium channel blocker, with a compound belonging to the ARB class, such a combination preparation may present additional problems in some cases, such as by causing drug-to-drug interaction and increased adverse side effects of individual drugs.
To this end, the inventors of the present invention have recognized problems of simple combination preparations of Amlodipine and ARB class compounds and conducted a variety of extensive and intensive studies to address the foregoing problems. As a result, the present invention has been completed.
[Related technique]
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